Clinical approaches to overcome PARP inhibitor resistance
Abstract PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effect...
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| Format: | Article |
| Language: | English |
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BMC
2025-05-01
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| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-025-02355-1 |
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| _version_ | 1849688191584436224 |
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| author | Yutian Zou Hanqi Zhang Pangzhou Chen Jiayi Tang Siwei Yang Christophe Nicot Ziyun Guan Xing Li Hailin Tang |
| author_facet | Yutian Zou Hanqi Zhang Pangzhou Chen Jiayi Tang Siwei Yang Christophe Nicot Ziyun Guan Xing Li Hailin Tang |
| author_sort | Yutian Zou |
| collection | DOAJ |
| description | Abstract PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors. |
| format | Article |
| id | doaj-art-e6b95246ea294a61a3e5692cbc9e6e80 |
| institution | DOAJ |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-e6b95246ea294a61a3e5692cbc9e6e802025-08-20T03:22:04ZengBMCMolecular Cancer1476-45982025-05-0124112510.1186/s12943-025-02355-1Clinical approaches to overcome PARP inhibitor resistanceYutian Zou0Hanqi Zhang1Pangzhou Chen2Jiayi Tang3Siwei Yang4Christophe Nicot5Ziyun Guan6Xing Li7Hailin Tang8State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterThe Sixth Affiliated Hospital, School of Medicine, South China University of TechnologyState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterDepartment of Pathology and Laboratory Medicine, Rainbow Boulevard, University of Kansas Medical Center, 3901 The Sixth Affiliated Hospital, School of Medicine, South China University of TechnologyState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer CenterAbstract PARP inhibitors have profoundly changed treatment options for cancers with homologous recombination repair defects, especially those carrying BRCA1/2 mutations. However, the development of resistance to these inhibitors presents a significant clinical challenge as it limits long-term effectiveness. This review provides an overview of the current understanding of resistance mechanisms to PARP inhibitors and explores strategies to overcome these challenges. We discuss the basis of synthetic lethality induced by PARP inhibitors and detail diverse resistance mechanisms affecting PARP inhibitors, including homologous recombination restoration, reduced PARP trapping, enhanced drug efflux, and replication fork stabilization. The review then considers clinical approaches to combat resistance, focusing on combination therapies with immune checkpoint inhibitors, DNA damage response inhibitors, and epigenetic drugs. We also highlight ongoing clinical trials and potential biomarkers for predicting treatment response and resistance. The review concludes by outlining future research directions, emphasizing the need for longitudinal studies, advanced resistance monitoring technologies, and the development of novel combination strategies. By tackling PARP inhibitor resistance, this review seeks to aid in the development of more effective cancer therapies, with the potential to improve outcomes for patients with homologous recombination-deficient tumors.https://doi.org/10.1186/s12943-025-02355-1 |
| spellingShingle | Yutian Zou Hanqi Zhang Pangzhou Chen Jiayi Tang Siwei Yang Christophe Nicot Ziyun Guan Xing Li Hailin Tang Clinical approaches to overcome PARP inhibitor resistance Molecular Cancer |
| title | Clinical approaches to overcome PARP inhibitor resistance |
| title_full | Clinical approaches to overcome PARP inhibitor resistance |
| title_fullStr | Clinical approaches to overcome PARP inhibitor resistance |
| title_full_unstemmed | Clinical approaches to overcome PARP inhibitor resistance |
| title_short | Clinical approaches to overcome PARP inhibitor resistance |
| title_sort | clinical approaches to overcome parp inhibitor resistance |
| url | https://doi.org/10.1186/s12943-025-02355-1 |
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